Identification of a recurrent transforming UBR5-ZNF423 fusion gene in EBV-associated nasopharyngeal carcinoma

Autor: Samantha Wm Lun, Grace Ty Chung, Fei-Fei Liu, Sai Wah Tsao, Ka Fai To, Kevin Yl Yip, Angela By Hui, Jeong-Sun Seo, Ken Ky Tso, Carol Y.K. Tong, Kwok Wai Lo, Chit Chow, Hyungtae Kim, Brian O'Sullivan, Nathalie Wong, John Ks Woo, Timothy Tc Yip, Raymond Wm Lung, Philippe Busson, Sau Dan Lee, Jessie Wf Yuen
Rok vydání: 2013
Předmět:
Male
Epstein-Barr Virus Infections
Recombinant Fusion Proteins
Ubiquitin-Protein Ligases
Population
Blotting
Western
Molecular Sequence Data
Transplantation
Heterologous
Nasopharyngeal neoplasm
UBR5–ZNF423 fusion
gene rearrangement
Mice
Nude
ZNF423
Biology
transcriptome sequencing
medicine.disease_cause
Real-Time Polymerase Chain Reaction
Transfection
Pathology and Forensic Medicine
Fusion gene
Epstein–Barr virus
Mice
oncogene
Cell Line
Tumor
medicine
Animals
Humans
Amino Acid Sequence
RNA
Small Interfering
education
In Situ Hybridization
Fluorescence
education.field_of_study
Nasopharyngeal Carcinoma
Reverse Transcriptase Polymerase Chain Reaction
Carcinoma
Proteins
Nasopharyngeal Neoplasms
Gene rearrangement
Oncogenes
Middle Aged
medicine.disease
Fusion protein
Molecular biology
Original Papers
DNA-Binding Proteins
Nasopharyngeal carcinoma
Female
Transcriptome
Zdroj: The Journal of Pathology
ISSN: 1096-9896
Popis: Nasopharyngeal carcinoma (NPC) is a distinct type of head and neck cancer which is prevalent in southern China, south-east Asia and northern Africa. The development and stepwise progression of NPC involves accumulation of multiple gross genetic changes during the clonal expansion of Epstein–Barr virus (EBV)-infected nasopharyngeal epithelial cell population. Here, using paired-end whole-transcriptome sequencing, we discovered a number of chimeric fusion transcripts in a panel of EBV-positive tumour lines. Among these transcripts, a novel fusion of ubiquitin protein ligase E3 component n-recognin 5 (UBR5) on 8q22.3 and zinc finger protein 423 (ZNF423) on 16q12.1, identified from the NPC cell line C666-1, was recurrently detected in 12/144 (8.3%) of primary tumours. The fusion gene contains exon 1 of UBR5 and exons 7–9 of ZNF423 and produces a 94 amino acid chimeric protein including the original C-terminal EBF binding domain (ZF29-30) of ZNF423. Notably, the growth of NPC cells with UBR5–ZNF423 rearrangement is dependent on expression of this fusion protein. Knock-down of UBR5–ZNF423 by fusion-specific siRNA significantly inhibited the cell proliferation and colony-forming ability of C666-1 cells. The transforming ability of UBR5–ZNF423 fusion was also confirmed in NIH3T3 fibroblasts. Constitutive expression of UBR5–ZNF423 in NIH3T3 fibroblasts significantly enhanced its anchorage-independent growth in soft agar and induced tumour formation in a nude mouse model. These findings suggest that expression of UBR5–ZNF423 protein might contribute to the transformation of a subset of NPCs, possibly by altering the activity of EBFs (early B cell factors). Identification of the oncogenic UBR5–ZNF423 provides new potential opportunities for therapeutic intervention in NPC. © 2013 The Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Databáze: OpenAIRE
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